The ultimate goal of this proposal is to investigate the degree to which chronic exposure to one drug of abuse (e.g. alcohol) may increase the propensity to self-administer another distinct type of drug (e.g. cocaine). The mesolimbic dopamine (DA) system appears to regulate, in part, the acute reinforcing properties of both ethanol (EtOH) and cocaine. The hypothesis of the present proposal is that chronic EtOH drinking enhances the reinforcing properties of cocaine as a result of neuroadaptations in the mesolimbic DA pathway. The intracranial self-administration (ICSA) technique has been used to reliably identify specific brain regions involved in the initiation of response-contingent behaviors associated with the delivery of a reinforcer. Thus, ICSA will be used to evaluate the reinforcing properties of cocaine in specific limbic brain areas. In addition, the microinjection-microdialysis paradigm has been successfully used to quantify neurochemical responses to the application of drugs of abuse to discrete brain regions. This technique will be used to measure DA-ergic response in the nucleus accumbens (Acb) following acute cocaine administration into the ventral tegmental area (VTA). The overall purpose of this study is to establish whether or not chronic EtOH drinking increases the sensitivity of the mesolimbic DA pathway to the reinforcing effects of cocaine in P rats, and if this increased sensitivity involves changes in DA transmission. [unreadable] [unreadable] [unreadable]